The classLandmark
Genetically lower CETP activity reduces dementia risk in a 1,091,775-person Mendelian randomization meta-analysis (Alzheimers Dement 2025)
Original title: Cholesterol-lowering drug targets reduce risk of dementia: Mendelian randomization and meta-analyses of 1 million individuals
To test whether genetically proxied non-HDL-cholesterol-lowering drug targets reduce all-cause dementia risk, researchers analysed 1,091,775 individuals from three prospective cohorts with individual-level data and two consortia with summary-level data, using genetic variants in HMGCR, NPC1L1, PCSK9, ANGPTL4, LPL and CETP as exposures in Cox regression and one- and two-sample Mendelian randomization. Meta-analysed one-sample Mendelian randomization odds ratios per 1 mmol/L lower non-HDL cholesterol were 0.24 (0.18-0.31) for HMGCR, 0.18 (0.12-0.25) for NPC1L1, and 0.30 (0.26-0.34) for CETP, with Cox regression and two-sample Mendelian randomization results mostly directionally consistent, while PCSK9, ANGPTL4 and LPL showed no clear effect. The authors conclude genetic lowering of non-HDL cholesterol via HMGCR, NPC1L1 and CETP reduces dementia risk, reflecting the effect of lifelong lower non-HDL cholesterol.
Original abstract
Introduction: We tested whether genetically proxied non-high-density lipoprotein cholesterol (non-HDL-C)-lowering drug targets reduce risk of all-cause dementia.
Methods: We included 1,091,775 individuals from three prospective general population cohorts with individual-level data and two consortia with summary-level data. We selected genetic variants within HMGCR, NPC1L1, PCSK9, ANGPTL4, LPL, and CETP associated with non-HDL-C. These variants were used as exposures in Cox regression and one- and two-sample Mendelian randomization. Results were meta-analyzed.
Results: Meta-analysis of one-sample Mendelian randomization odds ratios per 1 mmol/L (39 mg/dL) lower non-HDL-C was 0.24 (0.18-0.31) for HMGCR, 0.18 (0.12-0.25) for NPC1L1, 0.97 (0.70-1.35) for PCSK9, 1.66 (0.52-5.36) for ANGPTL4, 1.41 (0.63-3.16) for LPL, and 0.30 (0.26-0.34) for CETP. Cox regression and two-sample Mendelian randomization results were mostly directionally consistent.
Discussion: Genetic lowering of non-HDL cholesterol via HMGCR, NPC1L1, and CETP reduces the risk of dementia. This reflects the effect of lifelong differences in non-HDL cholesterol on risk of dementia.
Highlights: Variants in HMGCR, NPC1L1, and CETP reduce the risk of dementia via non-high-density lipoprotein cholesterol (non-HDL-C). An effect of PCSK9, ANGPTL4, and LPL variants on dementia risk cannot be excluded. This reflects the effect of lifelong lower non-HDL-C on risk of dementia.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.